Translating evidence: pain treatment in newborns, infants, and toddlers during needle-related procedures

Evidence and knowledge translation tools are available for preventing and minimizing procedural pain in newborns, infants, and toddlers. Improving pain management practices for this population must be a priority.


Introduction
Sick and preterm newborns are exposed to repeated invasive skin breaking painful procedures throughout their hospitalization, with no or minimal use of known effective pain management strategies. 9,10,12,28,31,34 Studies focusing on hospitalized children show similar information that hospitalized infants and children are exposed to frequent repeated painful procedures with inconsistent use of pain management strategies. 41,43,45 Safe and effective evidence-based strategies exist to reduce pain and distress during these frequently occurring painful procedures. Heel lancing is by far the most commonly performed painful procedure in hospitalized newborns and young infants, 28 whereas venipuncture, peripheral intravenous placement, and needle-related procedures classified as "needle pokes" are more commonly reported in hospitalized children. 43,45 In all likelihood, these numbers of recorded painful procedures underestimate the true burden of pain because they rely on clinical documentation and rarely account for the pain intensity of the procedure, number of attempts, length of the Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Carefully monitor need for bloodwork and other invasive
procedures. 2. Effective and safe pain treatment strategies during procedures for sick and healthy newborns and infants include breastfeeding, skin-to-skin care, and sweet solutions. 3. For toddlers during needle procedures, consistent use of (1) upright secure comfort holding by parents/caregivers; (2) age-appropriate distraction; and (3) topical anesthetics are recommended. Sweet solutions may also help to reduce pain and distress in this age group. 4. Involving and empowering parents/caregivers during painful procedures is crucial.
procedure, and skill of the health care provider. Preventing pain is the best way to reduce burden of pain. Each and every decision for ordering blood sampling for diagnostics and monitoring of current status needs to be carefully made, based on health status, need for monitoring, current treatment, and treatment plans. Reducing the number of invasive procedures without compromising the health of hospitalized newborns, infants, and toddlers needs to be a priority in all settings.
The following section outlines evidence-based strategies, based on synthesized evidence from systematic reviews, for reducing pain during painful procedures in newborns, infants, and toddlers (Box 1). This will be followed by knowledge translation initiatives in place to promote widespread use of knowledge, including system-wide and national and global strategies. For information regarding pain management for surgery and underlying diseases, including opioid analgesics, see Clinical Update Pediatric pain treatment and prevention for hospitalized children. 14 Note, "mother" is used and recognized in the context of breastfeeding and skin-to-skin care (SSC) as the birth parent throughout this update.

Pain management in neonates
There are 3 strategies that have been most extensively studied and shown to reduce pain in preterm and hospitalized term newborns during painful procedures. As summarized in Tables 1  and 2, these strategies are breastfeeding, 2,35 SSC, 23 and small volumes of sweet solutions (sucrose or glucose). 5,16,18,22,39 In addition, rocking and holding, swaddling and containment such as facilitated tucking, and nonnutritive sucking can be considered as adjuvant treatments to use in addition, especially when using sweet solutions. 29 Although less studied in the context of pain, the role of parents in providing developmental care interventions including gentle touch cannot be underestimated. 33 A discussion on the pain assessment methods used during these studies is beyond the scope of this clinical update focusing on translating effective pain treatment into action. However, pain outcomes reported are based on various well-accepted and psychometrically tested behavioral outcomes (crying duration, facial expressions of pain, and unidimensional composite pain scores), multidimensional composite pain scores, and less consistently, physiological indicators. 4 However, it is important to acknowledge that there is no gold standard of pain measurement, and it remains challenging to differentiate pain from stress in all ages, especially critically ill neonates. 4 2.1. Breastfeeding during painful procedures 2.1.1. Overview and mechanism of action Breastfeeding before and during short-lasting needle-related painful procedures, when possible, feasible, and culturally acceptable, reduces behavioral and physiological responses to pain. Mechanisms are considered multifactorial and include tactile stimulation through the SSC, smell, heartbeat, and chest movement of the mother, as well as sucking, the slightly sweet taste of breast milk, and possibly, endogenous opiates present in the breast milk. 2,35

Systematic review findings
The most recent Cochrane systematic review of breastfeeding for procedural pain reduction is now a decade old. 35 This review included 20 trials in total: 16 during heel lancing and 4 during venipuncture. All included healthy term or near-term newborns.
Ten studies focused on breastfeeding and 10 focused on expressed breast milk. Breastfeeding was shown to reduce pain based on crying duration, facial expression scores, composite pain scores, and heart rate changes from baseline. For example, duration of crying was able to be pooled for 5 studies, with results showing a mean difference (MD) of 241 seconds (95% confidence interval [CI], 250 to 233) in the breastfeeding group compared with no intervention. Similarly, the wellestablished multidimensional Premature Infant Pain Profile (PIPP) scores were pooled for 3 studies and showed significantly lower scores in the breastfeeding group compared with a group administered water (MD 26; 95% CI, 27 to 24) and compared with being held swaddled by mothers (MD 27; 95% CI, 29 to 26). However, the same analgesic effects were not seen with supplemental breast milk. As breast milk contains around only 7% lactose, which is the least sweet of the sugars (fructose . sucrose . glucose . lactose), 3 the mild sweet taste most likely contributes little to analgesia in isolation (eg, delivered by oral syringe or via pacifier).
More recently, Benoit et al. 2 published an updated systematic review and included 21 additional trials published from 2011 to 2016. Most procedures studied were heel lance (10), followed by intramuscular injection (6), of which 3 included infants beyond the newborn period. Three studies focused on pain during venipuncture and one each on eye examination and tape removal. Breastfeeding was the intervention in 14 studies and supplemental breast milk in 6 studies, and in 1 study, breastfeeding was compared with breast milk and sucrose. Findings were the same as above, with all studies comparing breastfeeding to other interventions reporting consistent analgesic effects during painful procedures but not for breast milk.
A commonly asked question concerns whether formula feeding similarly reduces pain. Only 1 study was included in the Cochrane systematic review of breastfeeding or breast milk for newborns, 35 which evaluated formula feeding compared with breastfeeding, no treatment, glucose, nonnutritive sucking, and holding. 44 This single study showed that formula feeding was equally as effective as breastfeeding. No such study was included in the more recently published systematic review. 2

Bottom line
If newborns are able to breastfeed, and breastfeeding is considered possible, feasible, and culturally acceptable during needle-related painful procedures such as heel lance, intramuscular or subcutaneous injections, venipuncture for blood sampling or venous line placement, breastfeeding should be considered as the first-line intervention. For this to occur, health care providers need to facilitate mothers to be present, comfortably seated, and able to be involved at the time of procedures and support them to breastfeed their newborn during procedures. As all studies to date have included healthy medically stable newborns, it is not known if breastfeeding in sick newborns is feasible and effective. Further studies are warranted in this area.

Overview and mechanism of action
Holding newborn infants SSC, with the infant wearing only a diaper, against a parents' chest before and during short-lasting, needlerelated painful procedures reduces behavioral and physiological responses to pain. Mechanisms are considered multifactorial and include tactile stimulation through the skin-to-skin contact, warmth, smell, heartbeat and movement of the mother, father, or other caregiver. Nearly all studies have focused on mothers. 23

Systematic review findings
A Cochrane systematic review of SSC for procedural pain reduction was published in 2017. 23 This systematic review included 25 studies with 2001 newborns; 18 studies include preterm and 7 included term newborns ( Table 1). Most studies (19, 76%) included focused on heel lance and included 1065 newborns. Four studies focused on intramuscular injection, one included both venipuncture and heel lance and one on tape removal. All except 2 studies focused on mothers only: 1 study compared mothers with fathers and 1 study compared mothers with an alternate female. Overall, results showed that SSC significantly reduced pain based on behavioral responses, heart rate, and composite pain scores. For example, PIPP scores during heel lance, at 30 seconds into the procedure, were pooled in a meta-analysis and showed a significant reduction for SSC compared with no treatment (MD 23.21, 95% CI, 23.94 to 2 2.47), and heart rate during heel lance was statistically significantly lower (211 beats/minute; 95% CI, 214 to 28) in the SSC group.

Bottom line
If preterm, sick, and healthy newborns are able to be held SSC during needle-related painful procedures such as heel lance, intramuscular or subcutaneous injections, venipuncture for blood sampling or venous line placement, SSC should be facilitated. For this to occur, health care providers need to facilitate mothers or other caregivers to be present, comfortably seated, and able to be involved at the time of procedures and support them to hold the infants SSC during procedures.

Overview and Mechanism of Action
The administration of small volumes of sweet solutions, specifically, sucrose and glucose, onto the infant's tongue 1 to 2 minutes before single, short-lasting painful procedures reduces pain during and after procedures. Sweet taste analgesia is thought to have 2 mechanisms: (1) immediate calming because of the strong (sweet) taste and (2) ongoing calming because of a sweet taste-mediated endogenous opioid release. 39

Systematic review findings
Sweet solutions are the most extensively investigated intervention for procedural pain relief in newborns. A number of systematic reviews have been published over the past 20 years confirming the effectiveness and safety of sucrose and glucose during different painful procedures in diverse populations of newborns and infants beyond the neonatal period 8,18,20,22,26,39 (Table 2). In the largest of these systematic reviews, a cumulative meta-analysis (CMA) involving all types of sweet solutions for newborns included 168 studies involving different painful procedures. Results demonstrated that sweet solutions reduced behavioral indicators of pain since the earliest studies published. 18 For example, CMA for crying time included 29 trials and 1175 neonates and showed a reduction in crying time of 23 seconds in favor of sweet solutions (95% CI, 229 to 218). When pain scores were standardized to a score out of 10, and pooled for meta-analysis, 50 trials with 3341 neonates were included. Results showed a statistically significant reduction of 0.9 (95% CI, 21.1 to 20.7).
In addition, Gao et al. 16 investigated the safety and efficacy of repeated administration of sucrose in a systematic review of 8 studies. Conclusions were made that sucrose continued to reduce pain during repeated episodes of painful procedures. Although no adverse effects of sucrose administration were reported, a subanalysis of 1 trial of repeated doses of sucrose during the first week of life reported that preterm infants ,31 weeks' gestational age who received .10 doses of sucrose daily had lower neurobehavioral scores at 36 weeks' gestational age compared with infants who received fewer sucrose doses. 24 These differences, however, had normalized by 40 weeks' corrected gestational age. Stevens et al., 37 in a larger study in which infants received sucrose or water for all procedures in the first month of life, found no differences in neurobehavioral outcomes. More recently, Campbell-Yeo et al. 7 evaluated sustained safety and efficacy of repeated doses of sucrose alone for all painful procedures over the course of a hospitalization compared with SSC alone and the combination of the 2 strategies. No differences in pain outcomes or neurobehavioral outcomes at 32 and 36 weeks' corrected gestational age were reported between the groups.
An important question over the years has focused on how much sucrose or glucose to use. Findings of the systematic reviews highlighted variability in sucrose and glucose concentrations and volumes used. However, in a multisite trial including 245 neonates, which evaluated 3 different volumes of 24% sucrose, the smallest volume of 0.1 mL was found to be just as effective as larger volumes during heel lancing. 38

Bottom line
Small volumes (0.1 mL) of sweet solutions (sucrose and glucose of at least 15%-20% concentration) are effective and safe for preterm and term infants during short-lasting frequently performed needle-related painful procedures. Only small volumes are required for analgesic effects (2-3 drops), administered on the top of the tongue, around 1 to 2 minutes before the procedure, just before the procedure, and repeated throughout the procedure if the infant shows signs of pain. The combination of sweet solution with nonnutritive sucking (NNS), SSC, facilitated tucking, and swaddling is recommended.

Pain management in infants and toddlers
The evidence for analgesic effects of pain management interventions during needle-related painful procedures for infants beyond the newborn period, and up to 2 years of age, is less robust than that for newborn infants. In addition, for toddlers, it is challenging, and often not possible, to discriminate pain from distress. Toddlers may demonstrate similar levels of distress to painful and nonpainful procedures or already be crying before a needle insertion, making accurate assessment of potentially effective pain management interventions difficult. 11 The reasons for such distress are multifactorial and relate to fears associated with unfamiliar environments and unfamiliar people, parental separation, and being positioned lying down during procedures. For example, in a trial of sucrose in children aged 12 to 36 months, most of the children were already crying at baseline, before the insertion of the cannula. 30 Regardless, there is evidence of strategies that have been shown to reduce pain in infants beyond the newborn period. In addition, there are strategies with evidence of analgesic effects in older children, which may also be assumed to reduce pain in younger children. In the following section, evidence for the following strategies will be summarized: sweet solutions, breastfeeding or formula feeding, topical anesthetics, upright secure holding, and distraction. As per newborn pain management, supporting parents/caregivers to be involved during painful procedures is essential. 17

Sucrose during painful procedures
As shown in Table 2, the most recent systematic review of sweet solutions (sucrose and glucose) for infants beyond the newborn period up to 1 year of age focused only on vaccination pain. 22 Findings highlighted that, as long as solutions were sufficiently sweet, small volumes of sucrose or glucose reduced crying duration during vaccination, by 21 seconds, and in the 3 minutes after vaccination, by 14 seconds. Sucrose or glucose can therefore be recommended for this age group. For maximum analgesic effects, however, repeating the dose is recommended shortly or just before commencing the procedure to ensure sustained analgesic effects.
For children older than 12 months of age, a systematic review of 8 trials published up to June 2014 and including 808 children  PAIN Reports ® found that the evidence was inconclusive for toddlers, and there was no evidence of efficacy for children older than 4 years of age. Since the publication of the systematic review, further studies have focused on toddlers. 13,25,30 For example, 2 studies of sucrose during vaccination in children aged 15 months 13 and 10 to 18 months 25 reported statistically significant reductions in crying duration. Mean crying duration in the sucrose group was 18 seconds compared with 33 seconds in the control group in 15-month children 13 and 52 seconds (SD 23) compared with 65 seconds (SD 19) in the control group in 18-month children. 25 In addition, Modanloo et al. 30 evaluated sucrose compared with water in 95 hospitalized toddlers during venipuncture, with topical anesthetic as the control condition. Sixty-one toddlers (72%) were aged 12 to 24 months and 24 (28%) were aged 24 to 36 months. Overall, sucrose did not statistically significantly reduce crying time or pain scores, and most infants were crying at baseline, before insertion of the needle.

Breastfeeding during painful procedures
As shown in Table 1, a systematic review of breastfeeding for needle pain beyond the newborn period, up to 1 year of age, included 10 studies with 1066 infants. All 10 studies focused on vaccination pain. 19 Pooled data showed that breastfeeding clinically and statistically significantly reduced duration of crying time by 38 seconds and standardized mean pain scores by 1.73/10 during the vaccination procedure. 19 Breastfeeding infants during vaccination can therefore be recommended. However, only 2 studies included infants older than 6 months; therefore, the evidence for efficacy, and also availability and feasibility of breastfeeding older infants and toddlers, is less well known. No studies in the systematic review compared bottle feeding with either formula or expressed breast milk. More recently, breastfeeding and bottle feeding with formula were compared in a study of vaccination pain in infants. 42 Similar reductions in crying duration and pain scores were reported for both breastfeeding and bottle feeding compared with no treatment, highlighting that pain reduction with bottle feeding may also be because of the close contact between the caregiver and the infant, despite not being attached to the breast. Bottle feeding can therefore be recommended for when breastfeeding is not able to occur. To date, no studies outside the vaccination context have been identified. The efficacy, effectiveness, feasibility, and acceptability of breastfeeding older infants and toddlers during painful procedures other than vaccination is therefore not known. However, when possible, feasible, and practical, breastfeeding or bottle feeding could be considered for nonurgent needle procedures, depending on feeding practices and parent preferences, up to around 12 months of age.

Physical and psychological strategies during painful procedures
A systematic review of nonpharmacological management of infants' and young children's procedural pain included strategies with some, but limited, evidence of effectiveness for older infants and young children. 32 Strategies with evidence of effectiveness included nonnutritive sucking (2 studies), touch or massage (2 studies), distraction with videos (2 studies), and structured nonparent distraction (1 study). However, both massage and nonparent distraction were no more efficacious than oral sucrose. Distraction by parents (6 studies) and distraction with toys (4 studies) were not shown to be effective. Most studies were considered low-to very low-quality evidence. Although upright holding was not specifically considered in this review, when possible and feasible, infants and toddlers should be securely held in an upright position to reduce distress by enhancing children's sense of control. 14,40

Topical anesthetics
A systematic review of pharmacological strategies for vaccination pain included 15 studies of topical anesthetics in children ,12 years of age. 36 A meta-analysis including 13 studies and 1424 infants showed a mean reduction of standardized acute distress scores of 0.91 (95% CI, 21.36 to 0.47) with topical anesthetics when administered before vaccination. 36 Topical anesthetics were therefore recommended during vaccination for infants and young children, and topical anesthetics during needle procedures are included in national and international recommendations for reducing pain during needle procedures. 40 Depending on the brand used, the agents need to be left on the skin for 30 to 60 minutes for maximum analgesic effects. Table 3 includes a summary of evidence-based recommendations of pain management strategies.

Partnering with parents during painful procedures
Involving and empowering parents during painful procedures is essential to minimizing pain and distress. As per the previous section, breastfeeding, SSC, secure comfort positioning, and simply being present require parents to be involved, informed, and empowered and play a fundamental role in recognizing their child's pain. 15 Parents report wishing to learn about pain and being involved during painful procedures. 6,27 Implementing organized approaches such as family-integrated care, with a focus on pain management, may facilitate parents consistently taking more active roles with their health care providers. 1

Implementing the evidence
Shifting knowledge into consistent action across diverse settings where newborns and young children undergo painful procedures requires producing knowledge into "usable" evidence, in the form of knowledge translation products, and coordinated efforts at local, national, and international levels. Usable evidence includes child, parent, and clinician-targeted knowledge translation products, such as videos, booklets, and position statements. Examples of child, parent/caregiver, clinician, and organizational-targeted knowledge translation products and initiatives are summarized in Table 4. These include a series of parent-targeted videos and written information, targeted at parents of newborns and young infants. In addition online web sites with embedded videos, patient and clinician stories, and recommendations on working collaboratively to reduce pain and stress during painful procedures.

Conclusion
Hospitalized newborns, infants, and young children require large numbers of painful needle-related procedures. There is robust evidence of analgesic effects of breastfeeding, SSC, and small volumes of sweet solutions for newborns. Although less robust, sufficient evidence exists of breastfeeding, sweet solutions, topical anesthetics, secure comfort positioning, and distraction for infants beyond the newborn period. For toddlers, it is difficult to discriminate between pain and distress; however, topical anesthetics, secure upright comfort positioning, and distraction during needle procedures are recommended. For all ages, supporting and empowering parents and caregivers to be present and involved is essential. Coordinated organizational, national, and global knowledge translation initiatives targeted at parents and clinicians aim to move knowledge into consistent use in diverse settings where infants and young children require painful procedures. Evidence and knowledge translation tools are available for preventing and minimizing procedural pain in newborns, infants, and toddlers. Improving pain management practices for this population must be a priority (Box 1).